Molecular signatures and lineage diversification of neurogenic and gliogenic radial glia in the gyrencephalic ferret cortex

Human exceptional cognition stems from evolutionarily derived cortical adaptations that drive expansive neurogenesis. In this study, we employ the gyrencephalic ferret model to systematically characterize the molecular profiles and lineage dynamics of cortical radial glia (RGs). By applying scRNA-Seq to ferret and human cortices, we identify conserved regulatory programs underlying cortical neurogenesis and gliogenesis in mammals. Through integrated scRNA-Seq, BrdU labeling, and immunohistochemical approaches, we show that, similar to their human counterparts, ferret cortical outer radial glia (oRGs), exhibit enhanced ERK and PKA signaling. ERK and PKA act in a mutually reinforcing manner to boost oRG self-renewal and neurogenesis, while inhibiting gliogenesis and prolonging the neurogenic period. Furthermore, we identify regional specialization within cortical gliogenic RGs: YAP/TAZ activation drives ventricular zone truncated radial glia (tRGs) toward ependymal glial fate in medial cortex, whereas SHH signaling instructs lateral cortical tRGs to generate tripotential intermediate progenitor cells, which serve as a shared source of astrocytes, oligodendrocytes, and cortically-derived olfactory bulb interneurons. Our findings support a model in which mammalian cortical neurogenesis, gliogenesis, and evolutionary expansion are co-regulated through an integrated signaling network orchestrated by ERK, PKA, YAP/TAZ, and SHH. This network relies on a precisely balanced interplay of mutual inhibition among these pathways to ensure proper developmental outcomes.